1. Field
The present disclosure relates to antibodies specifically binding to c-Met, fragments thereof, and a use of the antibodies.
2. Description of the Related Art
Hepatocyte growth factor (HGF) is a mesenchyme-derived pleitrophic cytokine that can induce mitogenesis, motogenesis, morphogenesis, and angiogenesis on various normal cells and tumor cells by binding to the extracellular region of a specific tyrosine kinase receptor, c-Met. Regulation of HGF/c-Met signaling pathway is implicated in various mechanisms related to cancer, such as tumor progression, metastasis, migration, invasion, and angiogenesis. In addition, c-Met amplification or mutation is thought to drive ligand-independent tumorogenesis. Thus, c-Met has recently emerged as a new target for anti-cancer therapy.
In particular, c-Met is known to be involved in induction of resistance to commonly used anti-cancer drugs, and thus, is regarded as an important player in personalized treatments. Representative anti-cancer drugs targeting epidermal growth factor receptor (EGFR) (ERBB1), such as Erbitux and Tarceva, work by blocking signal transduction related to a cancer development. Herceptin, which is a well-known breast cancer drug, targets ERBB2 (HER2) and works by blocking signal transduction necessary for cell proliferation. However, recent findings have indicated that among patients resistant to the drugs described above, anti-cancer drugs do not work due to overexpression of c-Met and activation of other types of signal transduction that leads to cell proliferation. Thus, many pharmaceutical firms are developing anti-cancer drugs to inhibit c-Met.
The related art discloses therapeutic antibody drugs that bind to c-Met to inhibit signal transduction that leads to cancer development.
Monoclonal antibodies against c-Met have been developed to prevent the interaction between the receptor and its cognate ligand, HGF. However, binding of these antibodies to c-Met induces dimerization of the receptor, and therefore, the antibodies have tended to have agonistic rather than antagonistic properties. This is due to the bivalent structure of the immunoglobulins, which act as natural dimerizing agents for the tyrosine kinase receptors. A ‘one-armed’ antagonistic antibody against c-Met has been described that consists of a monovalent Fab fragment with murine variable domains for the heavy and light chains fused to human IgG1 constant domains. The antibody is prepared through a genetic recombinant method, and is currently in clinical trial. However, this antibody is effective only when the treatment is performed in combination with chemotherapy; when the antibody is used as a single agent, anti-cancer effects are relatively low. Therefore, despite significant advancement in treatment of cancer, there is still a need to develop new therapeutic antagonistic antibodies against c-Met.